There has been a dramatic (3-4 fold) increase over the past 50 years in the ingestion of the n-6 essential polyunsaturated fatty acid (PUFA), linoleic acid (LA) with the addition of vegetable oil products (soybean, corn, palm, and canola oils, as well as margarine and shortenings) to the Western diet. More recently, there has been an intense debate regarding the health impact of that increase and whether a particular dietary PUFA recommendation (to consume 5-10% of energy as predominantly LA) is benefiting or harming people in Western nations such as the US. LA is converted to the long chain (LC-) PUFA arachidonic acid (ARA, 20:4n- 6) utilizing three (2 desaturation and 1 elongation) enzymatic steps, and ARA then can be converted to pro- inflammatory eicosanoids by lipoxygenase, cyclooxygenase and p450 enzymes. Encoded for by two fatty acid desaturase genes (FADS1 and FADS2) that sit next to each other in the FADS cluster (11q12.2-q13.1), the activity of two key desaturases are the rate limiting steps in ARA biosynthesis. Key observations from the literature and our own preliminary data reveal that gene variants in the FADS cluster are associated with an increased capacity to produce LC-PUFAs and with the production of CVD biomarkers, including LDL, triglycerides, HDL, total cholesterol, CRP, enzymatically- and nonenzymatically- generated eicosanoids, and with clinical CVD. Importantly, African American populations have much higher frequencies of FADS risk alleles, produce more LC-PUFAs including ARA, and exhibit higher levels of both CVD and coronary artery disease biomarkers. Taken together, these studies demonstrate a desperate need to conduct studies across many racial/ethnic groups and emphasize that understudied populations create a simultaneous challenge and opportunity to understand the impact of the dramatic increase in dietary LA on human health. Consequently, the goals of this revised R01 application in response to the RFA titled `Nutrigenetics and Nutrigenomics Approaches for Nutrition Research' (PAR-13-375) are to: i. provide the first comprehensive investigation of the role of FADS genetic determinants on PUFA biosynthesis and metabolism as well as levels of inflammatory markers in a controlled dietary environment using two (low LA and high LA) parallel diets; ii. substantially improve our understanding of ethnic-specific gene*diet interaction(s) with a direct comparison of African American and European American individuals in the setting of a controlled dietary environment; and iii. improve our understanding of health outcomes by examining whether the association between variants in the FADS gene cluster with levels of PUFAs in plasma phospholipids and CVD/risk factors differs by race/ethnicity in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. We will leverage the expertise of, and pre-existing collaborations among six major medical centers to answer essential questions to close the gap in our understanding of the influence of the increase in dietary LA on the health of diverse populations, and of whether current dietary recommendations are contributing to observed health disparities.